dr.

Khomimah, SpPD
RS Islam Jakarta Pondok Kopi

SEPSIS

Epidemiologi dan
Definisi
Sepsis :
Kondisi yang ditandai oleh sindroma respons
inflamasi sistemik / systemic inflammatory
respon syndrome (SIRS) sebagai akibat
proses infeksi seperti bakteri, viral, jamur
SIRS:
Respos inflamasi dapat disebabkan proses
non-infeksi (trauma berat, komplikasi
operasi__insufiseensi adrenal, infark
miokard, luka bakar, pankreatitis akut

Bone et al. Chest 1992;101:1644

 Sepsis

berat

Sepsis yang disertai disfungsi organ.

hipoperfusi hipoksemia jaringan

Syock

sepsis

Hipoperfusi yang diakibatkan sepsis yang

menetap meskipun sudah dilakukan

resusitasi cairan dengan adekuat
Akibat sepsis berat yang tidak teratasi

/ SIRS

Kaskade gangguan
yang diinduksi sepsis

Levy

et al 2005

 Angka

kematian: tinggi

Insidensi

sepsis meningkat:

Populasi tua meningkat

Penurunan sistem imun akibat kmoterapi
Transplantasi organ
Tindakan invasif
ko-morbid : DM, HIV, CHF

Inggris:
Insidensi sepsis berat yg masuk ICU 1,5 % /tahun
Angka kematian 23 30 kematian per 100.000 populasi
1/3 pasien CU sepsis (25%-nya sepsis pada saat di bangsal

rawat)

Number or sepsis case in US according

to causative microorganism 1979-2001

Martin et al, NEJM 2003; 348:154

Clinical conditions associated with sepsis

Gastrointestinal
Liver
Gallbladder
Colon
Intraabdominal abscess
Intestinal obstruction
Intraabdominal instrumentation
Genitourinary
Acute pyelonephritis
Renal abscess
Renal calculi
Urinary tract obstruction
Prostatic abscess
Instrumentation
Pelvic
Pelvic abscess, peritonitis

Intravascular
Central iv line
Infected prostetic device
Septic thrombophlebitis
Lower respiratory tract
Community acquired pneumonia
Nosocomial pneumonia
Empyema
Lung abscess
Cardiovascular
Acute bacterial endocarditis
Myocardial abscess
Central nervous system
Bacterial meningitis
Brain abscess
Perimeningeal infection
Cuncha B. In : Conn Current Therapy 2003

1. Respon inflamasi
Respon fisiologi pada sepsis
Tujuan: mengeliminir patogen atau
toksin
Keseimbangan homeostasis
Sepsis efek sistemik

Gambar 2. Perkembangan
sepsis

2. Gejala dan tanda awal

sepsis
jaringan/sel hipoksia respirasi anaerobik
selular produksi laktat meningkat penurunan PH darah
/asidosis (keseimbangan asam basa berubah) stimulasi
medulla oblongata peningkatan frekuensi napas

Hipoperfusi

Vasodilatasi

sistemik (pasien tampak merah dan flushed).

Peningkatan sirkulasi perifer dan permeabilitas
mikrovaskular ekstravasasi cairan dari sirkulasi
volume intravaskular turun disfungsi organ

Peningkatan

frekuensi napas dan heart rate, perubahan

status mental, produksi urin turun, TD turun, dan
perubahan temperatur

awal sepsis: vasodilatasi venous

return dan cardiac output turun heart
rate dan kadar adrenalin meningkat
(kompensasi) perbaikan cardiac out
put dan tonus vaskular

Fase

Respons

penurunan aliran darah: Aktivasi

sistem RAA tonus vaskular meningkat
dan penurunan produksi urin
(mempertahankan volume cairan tubuh)

 Tahap

lanjut:

sebagai dampak hilangnya venous return

dan volume sirkulasi darah suplai

oksigen tidak adekuat, hipoksia selular
dan disfungsi organ.
Gejala perburukan ini dalam beberapa jam
sebelum sepsis berat

awal terlewat sepsis

berat/shock septik

keluhan

3. Sepsis, sepsis berat, dan

shock septik

Systemic Inflammatory Response Syndrome (SIRS)

Host response to
Inflammation include 2 of:
1. Temp >38oC or <36oC
2. Heart rate >90x/
3. Respiratory rate >20x/
or PaCO2<32mmHg
4. White blood cells count
>12.000/mm3, < 4.000
or bands >10%
Bone et al. Chest 1992;101:1644

Kriteria klinis sepsis

berat
Sepsis
berat

Sepsi
s

tanda sepsis
yang
berhubungan
dengan disfungsi
organ

Fungsi paru (hypoksia)

Fungsi ginjal (peningkatan

serum kreatinin)
Koagulasi ( trombosit turun,
DIC)
Fungsi hati
(hiperbilirubinemia)
Status mental

 Syok

septik

Dampak lanjut respon inflamasi sistemik

terhadap suplai oksigen jaringan

Harus diterapi sebelum kerusakan organ
menetap
Tidak berespon terhadap terapi
pengganti cairan

Syok refrakter
Tekanan darah tidak berespon terhadap

obat vasoaktif kematian

CCP/SCCM A Consensus Conference

Definitions of Sepsis, Severe sepsis and
Septic shock

Systemic Inflammatory Response syndrome

(SIRS)
Sepsis
Severe sepsis
Septic shock
Multiple Organ Dysfunction Syndrome (MODS)

Bone RC, et al (1992): American College of Chest Physician / Society of

Critical care medicine Consensus Conference

DIC Scoring
Platelet count
> 100.000 = 0 < 50.000 - 100.000 = 1 <
50.000 = 2
D-dimer
0.5-1 = 1
1-2 = 2
> 2 ug/ml = 3
PT/APTT
Prolong PT
3-6 sec = 1
>6
sec=2
Fibrinogen
< 100 = 1

ISTH 2001

MANAGEMENT

Basic concept and Novel Strategy

in Managing Sepsis

Elimination source of infections

Antibiotic treatment

Supportive care : Stabilized the patient

Maintain oxygenization and perfusion
Nutrition, renal function, coagulation, etc

Modulation the immune response

Hyperimmune state or immunoparalysis

Strategy in Management of Sepsis

Supportive
Immunosupresion
Antimicrobial
Sepsis

Underlying diseases and risk factor

Immunostimulation
Outcome

days

Surviving sepsis campaign guidelines for

management of severe sepsis and septic shock
A.
B.
C.
D.
E.
F.
G.
H.
I.
J.
K.

Initial Resuscitation
Diagnosis
Antibiotic therapy
Source Control
Fluid Therapy
Vasopressors
Inotropic Therapy
Steroids
Recombinant Human
Activated Protein C
Blood Product
Administration
Mechanical Ventilation of
Sepsis-Induced Acute
Lung Injury

Sedation, Analgesia, and

Neuromuscular Blockade
in Sepsis
M. Glucose Control
N.
Renal Replacement
O.
Bicarbonate therapy
P.
Deep Vein Thrombosis
Prophylaxis
Q.
Stress Ulcer Prophylaxis
R.
Consideration for
Limitation of Support
S.
Pediatric consideration
Dellinger RP - Crit Care Med 2004; 32(3): 858-73
L.

Factors that determine the outcome of

sepsis treatment
Virulence of the pathogens
Early management and appropriate treatment
of primary causes (source of infections and
antimicrobial treatment)
Early management and quality of supportive
treatment
Underlying diseases
Host response to infection
Opal, Shock 2003

RESUCITATION

Resucitation
In case of severe sepsis, hypotension
or shock
Early in 6 hour period
Fluid therapy, oxygenization, vasopressor
Transfusion if needed
Monitoring
Rivers E, Nguyen B, Havstad S, et al. N Eng J Med 2001;345:1368-77

Monitoring in Sepsis
Monitoring is essential in unstable
conditions (severe sepsis or shock)
Clinical examination and
assessment
cant be substituted by invasive
monitoring
Minimal requirement include
blood pressure, continuous cardiac
monitoring, central venous
pressure,
Lynn WA.
In: Amstrong D, Cophen J. Infectious Diseases, 1999.
rapid blood gas analysis

Goals of Resuscitation
Central

venous pressure 8-12

mmHg
MAP > 65 mmHg
Urine output > 0.5mg/kg/hours
ScvO2>70%

ng sepsis campaign guidelines for management of severe sepsis

ptic shock. Crit Care Med 2004; 32(3): 858-73

Oxygen transport and

utilization parameters
Oxygen

delivery (DO2)
CO x CaO2 x 10
CaO2= 0.0031 x PaO2 + 1.38 x Hb
x SaO2

Oxygen

consumption (VO2)
VO2=CO x Hb x 1.38 x (SaO2SmvO2) x 10

ScvO2/SmvO2
Central

venous/mixed venous oxygen

saturation
Oxygen saturation from central venous
catheter or pulmonary artery catheter (Swan
Ganz)
Reflects physiologic efforts to meet oxygen
demand
Normal value : 65-75%
SmvO2 <50% : body limit of aerobic
metabolism
lactic acidosis

Fluid treatment in septic

shock
Fluid resuscitation may consist natural or
artificial colloids or crystalloids
There are no evidence-based support for
one type of fluid over another
Resuscitation with crystalloids require
more volume to achieve the same end
point
For fluid challenge need 500-1000 ml of
crystalloids or 300-500 ml colloids over 30
minute and repeated based on response

ng sepsis campaign guidelines for management of severe sepsis

ptic shock. Crit Care Med 2004; 32(3): 858-73

CVP/PAWP and CO response

during fluid challange

Vasopressor in septic
shock
Criteria for

When to start?
Adequate cardiac
filling :
CVP/PCWP : 12-15
mmHg
Cardiac index>3-4
l/min/m2
ScvO2 >65-70 %
MAP <70 mmHg

effectiveness
MAP > 60-70 mmHg
No decrease in CI or
ScvO2
reestablishment of
urine flow
decreased blood
lactate level
adequate skin
perfusion
adequate level of
consciousness

Vassopressor:
norepinephrin or dopamine

Either norepinehprine or dopamine is the first

choice vasopressor to correct hypotension in
septic shock
Norepinephrine has vassoconstrictive effect,
increase MAP more potent than dopamine, less
effect to heart rate and splanic circulation.
Dopamine increase MAP and CO primarily due
to increase stroke volume and heart rate.
Epinephrine and is least agent suggested

Practical Use of
vassopressor

Norepinephrin:
Start dose 0.05ug/kg/min, increase step
of 0.05ug/kg/min up to MAP 70mm Hg
If NE > 0.1-0.2 ug/kg/min need invasive
monitoring with pulmonary arteri
catether
Dopamine :
Initial dose 5-10 ug/kg/min increased
gradually
Epinephrin:
Start dose 0.05ug/kg/min increase
0.05ug/kg/min

Protocol for Early Goal-Directed Therapy.

Rivers E. N Engl J Med 2001;345:1368-77

Survival Sepsis Campaign Guidelines for

management of severe sepsis and septic shock

IV

antibiotic therapy should be

started within 1 hour
GRADE E
Initial empiric anti-infective therapy
should have activity against the
likely pathogen (see local
susceptibility pattern)
GRADE D

General Concept in Emprical Antibiotics

Therapy

Spectrum of antibiotics
Organ system involved
Pharmacokinetics
Safety profile
Cost

Cuncha B. In : Conn Current Therapy 2003

Spectrum of antimicrobial
Pathogen possible (most likely)
Gram positive, negative, anaerobe, mixed,
parasite, fungal
Community or nosocomial infections
Resistance pattern
Host condition and Immunological status
Risk of antimicrobial failure

Organ system involved

Site infections

Pulmonary, abdominal, genitourinary,

cns, multiple, no obvious site
Focal infection
Prosthetic, abscess

Antimicrobial Pharmacokinetics
Antimicrobial blood levels
Antimicrobial tissue levels
Antimicrobial combination interaction
Drugs interaction

Safety profile
Organ dysfunction or failure
Side effect
Allergic potential
Drug induce fever
Resistance potential

Appropriate Antimicrobial Treatment

Initial treatment will improve survival
Decreased development of shock
Essential but others factor involved
on significant mortality decreasing.

Simon D, Crit Care Clin 2000;16(2):215

Single or Combination Antimicrobial Treatment

Covered potential pathogen
Synergistic activities
Special cases :
Endocarditis caused by Enterococcus
Nosocomial pneumonia by gram
negative rods
(P. aeruginosa)
Chronic osteomyelitis
Prosthetic material (prosthetic valve
endocarditis)
Neutropenic
Bouza E, Munoz P. Med Clin North Am. 2000;84(6):1357-87

Strategy for empirical

treatment
Patient

Outpatient

Hospitalized

Stable condition

Deescalation

Severe or high risk

Escalation

Antibiotic selection based on

Susceptibility and resistance pattern
Immunity status, co morbidity and organ dysfunction

Antibiotic monotherapy or combination

Pohan HT, 2005

General Concept in
Management of Sepsis

Elimination source of infection

Antimicrobial treatment
Supportive treatment
Modification the maladaptive
immune response

Sessler CN, Shepherd W. Curr Opin in Crit Care 2002;8:465-72.

Supportive Therapy in Sepsis

Oxygenization
Fluid and volume resucitation
Vasopresor and inotropic
Albumine
Blood trasfusion
Nutrition
Blood glucose controlled
Renal dysfuction
Bicarbonate therapy
Corticosteroids
Coagulation disorders
Jindal N, Hollenberg SM, Dellinger RP. Crit Care Clin 2000;16(2):233-49

Nutritional support
Nutritional support is important in septic
patients
Early nutritional support seems to be
beneficial in all acutely ill patients.
Enteral route is preffered to maintain
integrity of gut mucosa and avoid possibly
harmful effect of parenteral nutrition
Immunonutrition have beneficial effect
improving host response in acute disease,
but further study is needed to better
define which constituents should be

Dietary requirement in
sepsis
Daily

intake 25-30 kcal/kg usual

body weight
Protein 1.5-2.0g/kg/day
Carbohydrate fat ratio of 60:40 to
70:30

Perez J. Intensive Care Med. 2001;27 Suppl 1:S116-27

Glucose control

Following initial stabilization, patients with severe

sepsis and hyperglycemia who are admitted to
the ICU receive intravenous insulin therapy to
reduce blood glucose levels (grade 1B).
Validated protocol for insulin dose adjustments
and targeting glucose levels to the <150 mg/dL
range (grade 2C).
We recommend that all patients receiving
intravenous insulin receive a glucose calorie
source and that blood glucose values be
monitored every 1-2 hrs until glucose values and
insulin infusion rates are stable and then every 4
hrs thereafter (grade 1C).
We recommend that low glucose levels obtained
with point-of-care testing of capillary blood be
interpreted with caution, as such measurements
may overestimate arterial blood or plasma

Kaplan-Meier cumulative survival curves for

patients in the intensive & conventional
treatment groups: ICU & hospital

Van den Berghe G - Clin Cornerstone - 01-JAN-2003; 5(2): 56-63

Hemoglobin levels in
Severe sepsis
The optimum hemoglobin levels in severe
sepsis has not been specifically
investigated.
Transfusion requirement in trial suggested
Hb > 7-9 g/dl
Transfusion for septic shock (ScvO2<70%)
require Hematocrit levels > 30%

g sepsis campaign guidelines for management of severe sepsis

tic shock. Crit Care Med 2004; 32(3): 858-73

Indications and timing of dialysis for

acute renal failure: renal replacement vs
renal support
Renal
replacement

Renal support

Purpose

Replace renal
function

Support other
organs

Timing of
intervention

Based on level of
biochemical
markers

Based on
individualized need

Indications for
dialysis

Narrow

Broad

Dialysis dose

Extrapolated from
ESRD

Targeted for
overall support

Abdeen O. Crit Care Clin 2002;(2):223-47

Metabolic acidosis in
sepsis
Metabolic acidosis mortality:
Hemodynamics instability
inducible nitric oxide synthase (iNOS)
ekspression cytokine proinflamatory

Pedoto A. Am J Respir Crit Care Med 1999; 159:397402

Jensen JC. J Surg Res 1990; 49:350 353

Immunotherapy in Sepsis
Immunosupression or immunomodulation ?
When to start the treatment ?
Target to treat (endotoxin ?)
One agent of combination ?

Immune therapy in sepsis:

to balance between inflammation
and antiinflammation
SIRS
CARS
Inflammation
inflammation

Anti-

Some Immunomodulatory Therapy in Sepsis

Antiendotoxin therapy
Monoclonal or polyconal antibodies
LPS analog, LPS elimination
Specific mediators
anti TNF
TNF receptors
IL-1 RA
Coagulants (AT, activated protein C)
Tissue factor pathway inhibitors
PAF
Arachidonic metabolites
Bradikinin antagonist
Nitric oxide synthase inhibitors

Immunostimulation
Immunoglobulins
G-CSF
IFN
Immunonutrition
Non specific
Corticosteroids
Pentoxifillin
Hemofiltration

Vincent JL, Sun Q, Duboid MJ. Clin Infec Dis 2002;34:1084-93

Pathway and Mediators of Sepsis,

Potential treatment and RCT results
Pathway
RCT result
Exo/endotoxin
Not evaluated
Not evaluated
Negative
Innate immunity
Not evaluated
Not evaluated
Not evaluated
Not evaluated
Proinflammatory
Negative
Pathway
Negative
Not evaluated

Mediators
Superantigen TSS1

Treatment
Anti TSS

Streptococcal endotoxin

Anti Strep endotx

Lipoplysacharide

Anti LPS

TLR2 TLR4

TLR agonis

Monocyte- macrophge

GM-CSF, IFNg

Neutrophyl

GCSF

B cell (and Ig)

IgG

CD4 (Th1-Th2)
TNF-a

Anti TNFa

IL1b

IL-1b agonist

IL-6

IL-6 agonist
Russel, 2006

Pathway and Mediators of Sepsis,

Potential treatment and RCT results
Pathway
Treatment
Procoagulant
C
Positive
Negative
Negative

Mediators
RCT result
Decreased Prot C

Activated Prot

Decreased AT3

Antitrombin III

Decreased TFPI

TFPI

Increased-PAI-1
Not evaluated
Antiinflammatory
IL-10
Not evaluated
TNF a receptor
Not evaluated
Hypoxia
Hypoxiea induce factor
Positive
vasc growth factor
delivery
Negative
Not evaluated
Immunosupression
Lymphocyte apoptosis
Not evaluated

tPA
IL-10
TNF a receptor
EGDT
Supra normal
Eritorpoitin
Anticaspases
Russel, 2006

Failed in Clinical trial of Immune-modulator

Therapy
The experimental agent are ineffective
Doses are inadequate
Timing of intervention is inadequate
Patient population is too heterogeneous
(variability in genetic polymorphism)
Single therapies may be ineffective
Vincent JL, Sun Q, Duboid MJ. Clin Infec Dis 2002;34:1084-93

Positive Resuts of RCT trials

Group

Patient
NNT

Motality
ARDS
31 vs 40
Severe sepsis
33 vs 49
and septic shock
Severe sepsis
25 vs 31
and septic shock
Septic shock
53 vs 63
Crit ill surgical
10-11.1)
Medical ICU

861
11
263
6
1690
16
299
10
1548

46 vs 8
1200

Intervention group

Control

Low tidal vlume

High tidal vol

EGDT
Activated Prot C
Hydrocortisone+
fludrocortisone
Intensive insulin
thrapy
(glucose lev 4.4-6.1)
29
Intensive insulin

Usual therapy
Placebo
Placebo
usual glucose
control
(glucose lev
Russel, 2006
usual glucose

Applicable Immunotherapy
Corticosteroids

Activated Protein C
Granulocyte (G-CSF)
IvIg
Immune nutrition

* Not available in Indonesia

Effect of treatment with low doses of hydrocortisone

and fludrocortisone on mortality in patients with septic
shock
P =0.02
P =0.001

Annane D. JAMA. 2002 Aug 21;288(7):862-71

Efficacy and safety of recombinant human

activated protein C for severe sepsis

Bernard gr. N Engl J Med 2001;344:699-709